Professor and Vice-Chair, Department of Anatomy, UCSF
Research SummaryI have a longstanding interest in glycobiology and biological sulfation. The origin of this interest began 30 years ago with our investigation of molecular mechanisms involved in lymphocyte homing to lymph nodes. Our early experiments established that lymphocyte attachment to high endothelial venules in lymph nodes involves a calcium-dependent lectin-like receptor and carbohydrate-based ligands displayed on HEVs. We cloned the receptor, now known as L-selectin, and found a C-type lectin domain, thus confirming its lectin nature. We identified the HEV-ligands biochemically and showed that they contain 6-sulfo sialyl Lewis x as an essential recognition determinant for L-selectin binding. We subsequently identified the critical sulfotransferases within HEVs that elaborate the essential sulfation modifications of the ligands. HEVs with the same biochemical phenotype as in lymph nodes are also found in tertiary lymphoid organs (TLOs) that are associated with tumors. The presence of HEVs in tumor-associated TLOs is correlated with good outcomes for patients with breast cancer and melanoma, probably reflecting immunoprotection by the TLOs that are in proximity to the tumors.
Most recently, we have studied the involvement of autotaxin in lymphocyte homing. We showed that this extracellular enzyme (lysophospholipase D activity) is highly expressed in lymph node HEVs. Here, it produces extracellular lysophosphatidic acid, which stimulates the motility of lymphocytes and promotes their transendothelial migration across HEVs. The action of autotaxin constitutes a novel step in the multistep lymphocyte homing cascade. Autotaxin is frequently overexpressed in human tumors. There is considerable evidence that the enzyme regulates the motility of tumor cells and promotes their metastasis. The SULFs (SULF1 and SULF2) represent an extension of my interest in the regulation of sulfation at the cell surface. We cloned the human versions of these enzymes over 12 years ago. These enzymes are secreted act as neutral pH glucosamine 6-O-endosulfatases for heparan sulfate (HS) chains. By removing 6OS groups from glucosamine in HS chains, the SULFs mobilize growth factors/morphogens from HS sequestration and modulate multiple signaling pathways in the cells.
Over the past 12 years, we have been focusing on the role of the SULFs in cancer, triggered by our finding that one or both SULFs are commonly overexpressed in cancers. Following our initial studies of the SULFs in breast cancer and pancreatic cancer, we have focused on the study of these enzymes in non-small cell lung cancer (NSCLC). Our studies have documented widespread overexpression of SULF2 protein in human NSCLC tumors. Employing a series of tumorigenic lung cancer cell lines, we showed that SULF2 promotes the malignant properties of these cells in both in vitro and vivo assays, including the formation of xenograft tumors in nude mice. We have developed a very sensitive ELISA for SULF2 and have detected the enzyme in human blood. Current studies are directed at determining whether the SULFs could serve as cancer biomarkers in blood or other body fluids.
University of California, Berkeley, CA, B.A., 1966, Physics
Cornell University, Ithaca, NY, Ph.D., 1972, Neurobiology
University of California, San Diego, CA, Postdoc, 1972-76, Cell Biology
Assistant Professor, University of California, Anatomy
Associate Professor of Anatomy, University of California, San Francisco
Professor of Anatomy, University of California, San Francisco
Member, Program in Immunology, UCSF
Member, Biomedical Sciences Program, UCSF
Investigator, Cardiovascular Research Institute, UCSF
Program Member, Comprehensive Cancer Center, UCSF
Member, Steering Committee, NIH Consortium for Functional Glycomics
Vice-Chair and Executive Committee, Dept of Anatomy
Honors & Awards
- Phi Beta Kappa
- American Cancer Society Postdoctoral Fellowship
- Phi Kappa Phi
- NIH Career Development Award
Keynote address to Keystone Symposium on Complex Carbohydrates
NIH Merit Award